Milnacipran (cis-2-amino methyl-N, N-diethyl-1-phenyl cyclopropane carboxamide) is a psychoactive drug, which is a selective norepinephrine and serotonin reuptake inhibitor. It is used for the treatment of clinical depression and chronic pain especially fibromyalgia.
Milnacipran was first disclosed in U.S. Pat. No. 4,478,836. It is currently available as Savella® immediate release tablets in USA and is indicated for the management of fibromyalgia.
Milnacipran has demonstrated numerous adverse reactions in human clinical trials with tolerability decreasing with increasing dose (Puech A. et al., 1997, Int. Clin. Psychopharm, 12:99-108). Milnacipran may induce a locally mediated nausea via gastric irritation and the rapid onset of nausea was observed even prior to achieving peak plasma levels. An immediate release formulation of Milnacipran would not be suitable for a once-daily dosing regimen for treatment of depression and other related diseases due to Milnacipran's relatively short, half-life, which is 8 hours approximately.
Moreover, the currently available immediate release formulation of Milnacipran is not ideal for the treatment of health conditions that require Milnacipran doses equal or above 100 mg/day given either as once a day or twice a day due to high incidence of treatment-emergent side effects that leads to poor patient tolerance. Higher doses are required in the treatment of severe depression and other associated disorders. Milnacipran dosing regime of 100-250 mg daily was recently reported for the treatment of fibromyalgia (U.S. Pat. No. 6,602,911). It would be very difficult to reach the upper limits of the dose range using the currently available formulation due to the dose related treatment, emergent side effects and the need to titrate over a long period to reach the required dose.
Various approaches have been tried to develop controlled release pharmaceutical compositions of Milnacipran in order to lower the incidence and intensity of side effects, especially for higher dosages, and to lower or reduce the frequency of dosing.
U.S. Pat. No. 6,699,506 discloses a pharmaceutical composition with prolonged release, for oral administration of a single daily dose ranging from 60 to 140 mg of Milnacipran, having a multi-particulate form containing a plurality of microgranules each comprising an active microsphere containing a saccharose and/or starch nucleus of a size between 200 and 2000 μm and containing 150 to 1000 μm of Milnacipran and a binding agent, each microgranule being coated with a film having a base of at least one polymer insoluble in water but permeable to physiological liquids.
WO 2006/132307 provides a stabilized Milnacipran-containing composition in which Milnacipran or a salt thereof is allowed to exist in a porous carrier, packing a powder containing Milnacipran or a salt thereof in an HPMC capsule, or combining an additive which does not cause an interaction with Milnacipran with time.
WO 2006/088305 discloses a gastric-retentive controlled release mono-matrix tablet composition, comprising: a) at least one pharmacologically active substance; b) hydrogel-forming materials consisting of polyethylene oxide and at least one component selected from poloxamers and colloidal silica; and c) a carbon dioxide-generating material. The composition of the above application floats in gastric juice and can continuously release the active substance in the stomach at a constant rate for at least 2 hours.
U.S. Pat. No. 7,704,527 describes once daily Milnacipran modified release composition wherein release profile is characterized by a 0.05 to 4 hour lag time period during which less than 10% of the total Milnacipran dose is released into the stomach followed by a slow or extended release of the remaining drug within the intestine over a defined period of time. This patent discloses Milnacipran formulation comprising an extended release core of Milnacipran with one or more extended release excipient and a coating around the extended release core comprising a delayed release excipient.
US 2004/0132826 and US 2006/0024366 provide an extended release dosage unit of Milnacipran (optionally containing the immediate release portion) coated with delayed release coating. The Milnacipran composition, when administered orally, first passes through the stomach releasing from zero to less than 10% of the total Milnacipran dose and then enters the intestine where the drug is slowly released over an extended period of time.
There, still exists a need to develop controlled release pharmaceutical compositions comprising Milnacipran or pharmaceutically acceptable salts thereof that can provide alternative pharmacokinetic profiles in order to achieve the desired therapeutic effect and simultaneously eliminate or reduce the unwanted side effects.
Additionally there is a need to provide controlled release pharmaceutical compositions comprising Milnacipran or pharmaceutically acceptable salts thereof, wherein the composition provides release of at least 90% of Milnacipran between 8 to 20 hrs in vitro.
Thus the present invention provides controlled release pharmaceutical compositions comprising Milnacipran or pharmaceutically acceptable salts thereof, to control release of Milnacipran over prolonged period of time.